Ischaemia-induced neurochemical alterations are related to ion fluxes through the cell membranes and subcellular membranes, respectively. However, the factor of key importance in the development of an ischaemia-induced injury is the increase in the intracellular free calcium level. The ceasing of energy supply for the cell causes the loss of the cellular calcium homeostatis. The release of potassium elicits membrane depolarization inducing the opening of the potential-dependent calcium channels. The entry of calcium to the cell partially proceeds through these potential-dependent channels. On the other hand, the increase in the sodium permeability of the membrane induces an intense release of excitatory amino acids (glutamate, aspartate). The glutamate released activates the receptor-dependent calcium channels, permitting an additional calcium influx into the cell [J. Cereb. Blood Flow Metab. 9, 127 (1989)].
The influx of calcium to the cell (pre- and postsynaptic calcium influx) may initiate catabolic reactions. The increased intracellular calcium level elicits reactions significantly influencing the functions and integrity of the cell. (Such reactions are e.g.: lipolysis, proteolysis, decomposition of microtubules, excessive protein phosphorylation) [Central Nervous System Trauma, Chapter 37, pages 513-532 (1984)].
The mechanisms playing a role in the neurotoxicity of veratrine are similar to the ischaemia-induced neurochemical changes. Veratrine significantly increases the tetrodotoxine-sensitive (TTX-sensitive) sodium permeability. The membrane depolarization caused by a persistent sodium influx leads to calcium influx and intracellular calcium release.
In addition, veratrine-induced depolarization causes an intense release of glutamate and aspartate [Neurosci. Lett. 121, 251 (1991); and Brain Res. 528, 212 (1990)].
Thus, the inhibition of sodium and calcium channels may play an important role in the mechanism of action of cerebro-protective compounds. The use of the sodium channel blocker TTX proved to have an advantageous effect in the protection against ischaemic injury (see the last two references cited).
Therefore, compounds diminishing the pre- or postsynaptic calcium uptake or altering the calcium sequestration in the intracellular sites may bear a high therapeutic importance.
At present, calcium antagonists are used for the treatment of ischaemic injuries mainly on the basis of their vascular effects; however, it seems to be more and more important to realize that compounds with such a mechanism of action have to exert their antihypoxic, anti-ischaemic effects by inhibition of the calcium influx to the neurons.
Non-competitive NMDA antagonists such as MK-801 (disocilpine) [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine], which inhibit the excitatory amino acid receptor-dependent calcium channels and, consequently, protect from the increase in the intracellular calcium level [Stroke 21 (Suppl. IV), IV. 72-IV. 77 (1990); as well as J. Cereb. Blood Flow Metab. 9, 127 (1989)], are of therapeutic importance.